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Critical Care: Acute Lung Injury and ARDS


Monday, October 23, 2006

10:30 AM - 12:00 PM

HYPERCAPNIA IMPAIRS ALVEOLAR FLUID CLEARANCE VIA PROTEIN KINASE CASCADE SIGNALING

Istvan Vadasz, MD*, Laura A. Dada, PhD, Emilia Lecuona, PhD, Arturo Briva, MD, Lynn C. Welch, BS, Jiwang Chen, PhD and JacobI. Sznajder, MD

Northwestern University, Feinberg School of Medicine, Division of Pulmonary, Chicago, IL

PURPOSE: Hypercapnia occurs in a significant number of patients with COPD and ARDS, in part as a consequence of the "permissive hypercapnia" ventilation strategy. We observed that hypercapnia impairs alveolar fluid clearance by decreasing Na,K-ATPase function in alveolar epithelial cells, however the mechanism by which elevated levels of CO2 lead to decreased fluid clearance and inhibition of Na,K-ATPase function has not been elucidated.

METHODS: Alveolar fluid clearance was assessed in an isolated rat lung model. Na,K-ATPase activity and protein abundance in alveolar type II cell cultures were evaluated. Activity of protein kinases was assessed by immuno-blotting with specific phospho-antibodies and in vitro kinase assay.

RESULTS: Elevated levels of CO2 (60 to 120 mmHg) led to sequential activation of AMP-activated protein kinase (AMPK), protein kinase C-{zeta} (PKC-{zeta}) and c-Jun N-terminal kinase (JNK) within minutes of exposure in rat alveolar type II cells, while alveolar fluid clearance, Na,K-ATPase activity and membrane protein abundance were significantly decreased. These effects were prevented by pharmacological inhibition or overexpression of dominant negative AMPK, PKC-{zeta} or JNK.

CONCLUSION: We provide the first evidence that hypercapnia impairs alveolar fluid clearance via activation of a protein kinase signaling cascade in the alveolar epithelium, thus leading to the downregulation of the Na,K-ATPase.

CLINICAL IMPLICATIONS: Hypercapnia has deleterious effects on the alveolar epithelium, which may have significant implications in COPD and ARDS patients.

DISCLOSURE: Istvan Vadasz, None.






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